Paget disease of the bone is a common bone disease characterized by abnormal osteoclasts which are large, overactive, multinucleated and contain paramyxovirus-like nuclear inclusions. It is a relatively common disorder, with an estimated incidence of 3% in individuals over the age of 40. In the majority of patients, Paget disease is asymptomatic. The 5% of patients with symptoms have bone pain and a wide range of complications including increased fractures, deafness and neurological complications. The most devastating complication of Paget disease is malignant transformation of the bone. Although these transformations are rare, they contribute significantly to the morbidity and mortality of this disorder. The most frequent type of malignant transformation associated with Paget disease is osteosarcoma. In addition, Paget patients with osteosarcoma have a much worse prognosis than patients with osteosarcoma de novo. Osteosarcomas are believed to result from a series of genetic alterations which transform the osteoblast to a malignant state. Strong evidence that an important tumor suppressor gene involved in the regulation of the osteoblast lies on chromosome 18 has recently been generated (Dr. Marc Hansen's laboratory). Furthermore, the applicant (Dr. Leach) has generated genetic evidence that there is a locus for Paget disease in the same region of chromosome 18. Thus, the correlation between Paget disease and osteosarcoma has a strong molecular basis. It is hypothesized that this osteosarcoma tumor suppressor gene and the Paget predisposition gene are the same gene, or two tightly linked genes (i.e., a contiguous gene syndrome). The goal of this research is to identify this gene (or these genes) on chromosome 18 and begin to determine their role in both of these disorders. This proposal is part of an Interactive Research Project Grant (IRPG) developed to achieve this goal. Dr. Hansen's laboratory will utilize mitotic mapping methods in osteosarcomas, while Dr. Leach's laboratory will use meiotic mapping with numerous Paget disease kindreds. Identification of this gene (or these genes) is an important step towards the development of treatment for osteosarcoma and Paget disease.